Viral exacerbation of allergic lung disease is a significant cause of morbidity and mortality in asthmatics of all ages. Each year in the United States, asthma exacerbation accounts for 2 million emergency department visits, and 500,000 hospitalizations, and the overwhelming majority of severe asthma exacerbations in both children and adults are associated with respiratory viral infections. Vaccination is among the most cost- effective methods of reducing the burden of infectious disease. Thus, safe and effective vaccination of asthmatics against respiratory viruses would be of tremendous public health benefit. In the proposed studies, we will refine a candidate intranasal, inactivated respiratory syncytial virus (RSV) vaccine. We have selected RSV as a model pathogen based on its association with asthmatic disease, limited genetic variability, as well as the suitability of animal models. Our previous studies that this vaccine promotes protective immunity to RSV, without promoting vaccine enhanced disease observed with other inactivated RSV vaccines. In the proposed studies, we will use a rational vaccine refinement approach to evaluate the potential of an inactivated, nasally administered viral vaccine to prevent or attenuate viral asthma exacerbation. Accumulating evidence suggests that the early signals generated by the innate immune system control the nature of the adaptive immune response to vaccination. However, little is known about which signals in resident airway cells are critical for protective vaccine induced immunity. We hypothesize that the innate immune response generated by resident airway epithelial cells and dendritic cells generates an immune signature of proinflammatory signals, which in turn, control the development of the adaptive immune response. Our studies will focus on the following Specific Aims: 1) Define the innate immune signals induced by live versus inactivated RSV in airway epithelial cells and dendritic cells, as well as select adjuvants. 2) Identify the in vitro vaccine induced signals associated with vaccine-mediated efficacy in vivo. 3) Assess the efficacy of inactivated intranasal vaccines in viral exacerbation of asthma. To investigate these aims, we will use a combination of well-characterized in vivo animal models, as well as in vitro studies using epithelial cells from carefully phenotyped healthy and asthmatic patients. PUBLIC HEALTH RELEVANCE: Viral exacerbation of asthma is a significant burden on asthmatic patients of all ages, and the heath care system in general. Vaccination is among the most cost-effective methods of reducing the burden of infectious disease. Currently, no vaccines are available for the majority of viruses implicated asthma exacerbation, and thus, safe and effective vaccination of asthmatics against respiratory viruses would be of tremendous public health benefit.